The dosimetry of OARs is usually tumor site and volume dependent. It has been reported that the tumor site is a prognostic factor for morbidities and QoL for patients after receiving head and neck irradiation by conventional 2D-RT [15]. Unlike other head and neck cancer, NPC usually presents with high propensity of tumor infiltration into the skull base and bilateral neck lymph nodes; thus, elective irradiation with large fields from the level of the skull base to the infra-clavicular nodal area is mandatory, even in patients with an early clinical stage. Using SIB-IMRT composed of three fixed dose levels, with a higher dose per faction to GTV and two lower doses to cover the uniform subclinical or elective anatomic sites, we observed the major differences of dose-volume received by OARs in NPC patients depending on the GTV. GTV was observed to be significantly and positively correlated with the mean and/or maximal dose in most OARs concerned. Furthermore, as far as we know from the literature, this is the first report to show GTV to be the determining variable for acute/late toxicity and QoL of NPC patients treated by SIB-IMRT combined with chemotherapy.
The location and size of the primary tumor, lymph node staging, tumor laterality, treatment techniques, and anatomical changes during treatment have all been shown to be significant factors in terms of the actual dose received by OARs [16]. Mucositis is common for NPC patients receiving chemo-RT. The problems associated with mucositis include oral pain, odynophagia, impaired taste, and weight loss. Mucositis was known to have a dose-effect relation with RT; however, the ability of clinical or dosimetric parameters in predicting severe mucositis was still controversial, using IMRT technique [17, 18]. In the study of Li et al [19]., weight loss and V30Gy predict severe oral mucositis in NPC patients treated by concurrent chemo-IMRT. In contrast, the mean dose in the oral cavity was found to impact the duration of oral mucositis by Orlandi et al [20]. In treating NPC, the oral cavity was usually outside the CTV fields, but its mean dose still ranges 35-42 Gy using the IMRT or VMAT technique [21-23]. Without using the detailed dosimetric analysis for oral mucositis in current study, we observed GTV positively correlated with the mean dose in the oral cavity and was predictive of mucositis and its related problems, e.g. weight loss and analgesia used.
Xerostomia remains one of the most common late toxicities for NPC patients treated by chemo-SIB-IMRT. The severity of xerostomia is largely dependent on the dose/volume in the salivary gland in the radiation field [24, 25]. The incidence of grade 2 or greater xerostomia in our cohort was 28.4%, which was higher than that reported in the literature [11, 21]. The parotid mean dose was around 30 Gy in the study, which is compatible with other reports [26, 27]. We observed the mean dose in the parotids most significantly correlated with GTV. This is mainly due to the major overlap of the PTV with the deep lobes of the parotids. An overzealous effort in sparing the parotids can result in the under-dosing of part of the GTV which is at risk for local recurrence, especially in those with parapharyngeal space invasion or upper neck lymph node enlargement. Growing reports have demonstrated there is no direct dose-effect relationship between the parotid dose and xerostomia for NPC patients [28, 29]. The reasons might be that the parotid dose revealed in the pre-treatment plan was different from the actual dose received because of the positional change of the gland during the treatment process and the mean dose of parotid in most NPC patients beyond the dose constraints recommended from the QUANTEC guideline [30, 31]. In contrast, GTV was observed to be predictive of xerostomia in our study. In this scenario, the other major salivary glands, the submandibular glands, were taken into consideration because they were usually exposed to high-dose irradiation if large nodes existed at level II.
Progressive neck fibrosis, which might compromise neck movement and increases the risk of vasculopathy of the carotid artery or neuropathy, was common in NPC patients treated by conventional 2D-RT but has been markedly reduced by IMRT.32 The incidence of symptomatic neck fibrosis and cranial neuropathy was 3.2% and 1.8%, respectively, in our series, which is compatible with other reports [33, 34]. However, our patients with larger GTV beneath the sternocleidomastoid muscle still had a significantly higher risk of suffering from progressive neck fibrosis.
The determinants of radiation neuropathy in previous reports included T classification, total RT dose, fraction size, overall treatment time, receiving chemotherapy, and GTV. In these studies, the patients analyzed underwent heterogeneous RT techniques, varying from conventional 2D-RT, 3D conformal RT, to IMRT [34-36]. In contrast, with a consistent technique of SIB-IMRT in our series, we observed the pre-treatment variable of advanced T classification and larger GTV were significantly associated with the occurrence of radiation neuropathy.
Socio-demographic variables and RT techniques were observed to be the determinants of post-treatment QoL outcome for NPC patients in the literature [15, 37, 38]. Most of the reports were in cohorts either treated by conventional 2D-RT or a mixture of different RT techniques. Huguenin et al. observed that head and neck cancer patients with large target volumes (e.g. NPC) treated by 2D-RT suffered from more QoL problems, including dry mouth, sticky saliva, trismus, problems with teeth, and trouble eating, than those with small target volumes (e.g. glottis ca) [15]. They also observed that these symptoms did not have a high impact on global QoL or functional scales on the QLQ-C30 core questionnaire. In the current study, we also observed NPC patients with a large GTV had more symptom problems, including dyspnea, constipation, taste/smell, speech, social eating, opening mouth, dry mouth, and sticky saliva. Meanwhile, global QoL and most functional scales (except for role functioning) were not observed to be significantly correlated with GTV in our study.
There are growing reports supporting the therapeutic benefits in dosimetry, tumor control and QoL for NPC patients if re-planning could be conducted either for patients with GTV reduction or the geometric change of OARs during the treatment course of SIB-IMRT [39, 40]. Using SIB-IMRT techniques, the major benefit of re-planning, especially for those without significant body shape change, is to reduce the GTV during the treatment course, which might potentially reduce the dose to the OARs. In the study by Yang et al. [39], the authors reported NPC patients treated by SIB-IMRT would have better QoL in global QoL, role and social functioning and some symptom scales if re-planning was done. We believe our study could echo the need for re-planning, especially for those with GTV reduction during the course of SIB-IMRT in NPC patients.
It should be noted that there are some limitations in the study. First, as mentioned above, geometric changes of GTV and OARs during treatment were not determined and the actual dose received might have varied from the dose shown on the pre-treatment plans. Second, it was difficult to determine whether the toxicities measured were the result of RT, chemotherapy or both, or the result of the existing cancer.
In conclusion, for NPC patients treated by chemo-SIB-IMRT, we observed GTV was significantly associated with mean or maximal dose in most OARs concerned, and patients with higher GTV presented with more severe acute and late toxicities and more symptomatic problems as measured by QoL scales.